Knowledge of the relative contributions of innate and adaptive immunity in host resistance to pathogens is essential both to an understanding the basic immunological mechanisms involved and in the design of effective immunotherapies. We have employed targeted gene disruption approaches to define the role of specific components of the antibody- effector cell pathway in host susceptibility to the encapsulated fungus Cryptococcus neoformans and the trematode Shistosoma mansoni. Mouse strains deficient in the activation subunit of Fc receptors, FcRgamma, have significant defects in type I, II and III inflammation, and manifest specific alterations in their responses to these pathogens. In C. neoformans the role of IgG/FcgammaR interactions has been studied in a model of passive immunotherapy employing IgG switch variants of an anti-capsular GXM antibody. Thus, IgG1 antibodies are protective and require the expression of FcRgamma chain while IgG3 antibodies enhance infection in both FcRgamma-/- and wild-type strains, implying the existence of a novel IgG3 FcR. We will pursue these observations to determine 1) The contribution of individual FcRs on specific effector cells to the sub-class differences in protection, 2) The structure of the IgG3 FcR and its relationship to the known FcRs and 3) The signal transduction pathways triggered by IgG3 binding to its FcR. In S. mansoni infection, pathology results from sensitized CD4 cells triggering granuloma formation, fibrosis and subsequent circulatory impairment. B cell deficient animals or animals lacking FcRgamma show enhanced tissue responses to egg deposition. Egg granulomas are larger and fail to undergo down-modulation during the chronic phase of infection in both deficient strains. These studies suggest a novel and previously unappreciated role for antibody-FcR interactions in modulating T cell mediated reactions. In addition, B cell deficient mice are impaired in their ability to excrete eggs, independently of FcRgamma expression. We propose to extend on these results by 4) Characterizing the specific FcRs and effector cells responsible for the enhanced granuloma response, 5) Determining the antibody receptors responsible for egg excretion and 6) Investigating the generality of antibody-FcR interactions as modulators of T cell responses by characterizing contact sensitivity and DTH reactions in FcR deficient animals.